Recent studies have demonstrated that the intranasal administration of insulin acts to improve memory and has an effect on obesity [1-8].
However, other studies have shown that intranasal administration of insulin over an extended period, typically six months, results in antibodies being raised to insulin [9].
Whilst the authors of this publication argue that the raising of antibodies to insulin could be beneficial in terms of being protective of loss of beta cell function in individuals at risk of Type I diabetes, there is no recognition that raising a neutralising antibody response to insulin would be of particular concern in patients with obesity who may be at risk of developing Type II diabetes and where there is limited additional capacity for the pancreas further to increase insulin production. It would also be inappropriate to increase neutralising antibody levels to insulin in patients who already have insulin loss as this may worsen the condition.
It is an aim of the present invention to provide for the intranasal administration of proteins, such as insulin and insulin analogues, and in particular by the applicant's bi-directional methodology, as disclosed in the applicant's earlier WO-A-2000/051672, the content of which is incorporated herein by reference.
Delivery of vaccine antigens by the bi-directional methodology has been shown to date to provide an increase in the circulating antibodies when compared to intranasal administration by conventional nasal spray technologies, in particular nasal spray pumps. As such, a person skilled in the art would have contemplated that intranasal administration of insulin using bi-directional delivery technology should increase the immune response to insulin and other immunogenic proteins, which is contrary to the requirement for delivery of proteins and peptides to the CNS.
It is a particular aim of the present invention to provide for the intranasal administration of proteins, such as insulin and insulin analogues, in therapeutically-significant amounts to the olfactory bulb region in the upper posterior region of the nasal cavity, such that the proteins access the CNS and avoid being presented to the nasal associated lymphatic tissue (NALT) which includes M-cells, as encompassed by Waldeyer's ring, and in particular in the adenoids, and antigen presenting cells (APCs) which are widely distributed throughout the nasal mucosa, which would cause a neutralising antibody response. The posterior region of the nasal airway is that region which is posterior of the nasal valve NV, as illustrated in FIG. 1. The nasal valve comprises the anterior bony cavum which contains inferior turbinate erectile tissue and septal erectile tissue, which are supported respectively by compliant ala tissue and the rigid cartilaginous septum [10]. These elements combine to form a dynamic valve, which extends over several millimetres, that adjusts nasal airflow, and is stabilized by cartilage and bone, modulated by voluntary muscle and regulated by erectile tissue. The lumen of the nasal valve is the section of narrowest cross-sectional area between the posterior and anterior regions of the nasal airway, and is much longer and narrower dorsally than ventrally, and this lumen defines a triangular entrance which extends to the piriform region of the bony cavum. The nasal valve is lined in its anterior part with transitional epithelium, with a gradual transition posterior to respiratory epithelium. The nasal valve and anterior vestibule define roughly the anterior one-third of the nose.
The posterior region of the nasal airway is that region which is lined with respiratory epithelium, which is ciliated, and olfactory epithelium, which comprises nerves which extend downwards through the cribiform plate CP from the olfactory bulb OB and defines the olfactory bulb region, whereas the anterior region of the nasal airway is that region which is lined with squamous epithelium, which is not ciliated, and transitional epithelium. The olfactory epithelium extends on both the lateral and medial sides of the nasal airway which defines the olfactory cleft, and typically extends downwards about 1.5 to 2.5 cm.
The upper posterior region is the region above the inferior meatus IM, as illustrated in FIG. 1, and encompasses the middle turbinate, the middle meatus, the sinus ostia in infundibulum (ostia to maxillary, frontal and ethmoidal sinuses), the olfactory region, and the upper branches of the trigeminal nerve, and is that region which includes veins which drain to the venous sinuses that surround the brain.
As illustrated in FIG. 1, the posterior region of the nasal airway is the nasal region posterior of an imaginary vertical plane VERT which is located at a position corresponding to the lower angle of the anterior nasal aperture (aperture piriformis), which corresponds substantially to one-quarter of the distance between the anterior nasal spine AnS, which is a pointed projection at the anterior extremity of the intermaxillary suture, and the posterior nasal spine PnS, which is the sharp posterior extremity of the nasal crest of the hard palate and represents the transition between the nose and the nasopharynx, which corresponds to a distance posterior of the anterior nasal spine AnS of between about 13 mm and about 14 mm (Rosenberger [11] defines the distance between the anterior nasal spine AnS and the posterior nasal spine PnS as being 56 mm in eighteen year old boys and 53.3 mm in eighteen year old girls).
As further illustrated in FIG. 1, the upper region of the nasal airway is an upper segment of the nasal airway which is bounded by the cribiform plate CP and a horizontal plane HORIZ which is located at a position corresponding to one-third of the distance between the nasal floor NF of the nasal airway and the cribiform plate CP, which corresponds to a height of typically between about 13 and about 19 mm above the nasal floor NF (Zacharek et al [12] define the distance from the nasal floor NF to the cribiform plate CP as 46+/−4 mm).
The upper posterior region is thus that upper posterior region which is bounded by the above-defined vertical and horizontal planes VERT, HORIZ.
It is a further aim of the present invention to provide for the intranasal administration of proteins, such as insulin and insulin analogues, such that the proteins which are not absorbed into the CNS remain in solution and are not phagocytosed by immunogenic cells, such as the antigen presenting cells.
It is a still further aim of the present invention to provide for the intranasal administration of proteins, such as insulin and insulin analogues, and in particular where delivered as a powdered formulation, such that a minimal amount of associated endotoxin is delivered therewith, so as to avoid triggering the maturation of immature antigen presenting cells.
It is a yet further aim of the present invention to provide that the intranasal administration of insulin, in particular in the treatment of Alzheimer's disease and obesity, does not result in the exacerbation or precipitation of type II diabetes.